Comparison of Total Intravenous Anaesthesia Using Propofol With or Without Sufentanil in Laparoscopic Cholecystectomies

Summary Sufentanil is an excellent adjuvant in total intravenous anaesthesia (TIVA). The present study evaluates effec-tivenessof differentconcentrations of sufentanil mixed in propofol for TIVAin laparoscopiccholecystectomy. Sixty adult patients of ASA physical status I or II (randomly divided into 3 groups of twenty each) undergoing elective laparoscopic cholecystectomy were included in this randomised control study. At induction, patients in all groups received i.v. bolus of sufentanil 1 µg kg -1 and continuous infusion of propofol 100 µg kg -1 min -1 . Anaesthesia was maintained with propofol infusion titrated in a range of 75 to 125 µg kg -1 min -1 . Groups S1 and S2 received propofol with sufentanil added at 1 µg ml -1 and 2µg ml -1 concentrations respectively, while group P received propofol without sufentanil. Additional sufentanil boluses (10 µg) were given to patients in all groups when there was an increase in the heart rate by more than 20 beats per minute or mean arterial pressure by more than 15%above baseline. Perioperative haemodynamic parameters, recovery times and postoperative analgesia were compared across the three groups of patients. Haemodynamic parameters (heart rate, systolic and diastolic blood pressures) were not significantly differ-ent across the three groups of patients in the perioperative period. Fewer Group S2 patients required additional sufentanil boluses to maintain adequate depth of anaesthesia compared to other two groups. Group S2 patients had better post-operative analgesia ( p =0.01) but prolonged recovery time ( p =0.001) compared to the other two groups. Sufentanil mixed with propofol provides better haemodynamicstability in laparoscopic cholecystectomies, with lesser requirementfor additionalsufentanil boluses, and good postoperative analgesia.


Introduction
Total intravenous anaesthesia (TIVA) is an evolved concept of general anaesthesia, which obviates the need for volatileanaesthetics. Propofol, a sedative-hypnotic agent with excellent recovery characteristics at the end of infusion and additional anti-emetic property, has become the drug of choice for TIVA. Newer synthetic opioids (fentanylcongeners) provide excellent analgesia and hence are popular adjuvants in TIVA. Sufentanilhas been combined with propofol in TIVA for various types of surgeries due to its advantages like synergistic action with propofol, rapid induction,less cardiovascular and respiratorydepression, and rapid smooth recovery profile. [1][2][3] Additionally, early postoperative analgesia with intraoperative use of sufentanilhasbeen shownin previousstudies tobe better than that with fentanyl. 1 These properties can make sufentanilan excellent adjuvant to propofolinTIVAfor upper abdominal laparoscopic surgeries where the intraoperative haemodynamicfluctuations due to pneumoperitoneum and changes in patient position are better addressed.Sufentanil-propofolTIVAprovides clearheaded recovery of consciousness at emergence compared to inhalationalanaesthesia and good postoperative analgesia, thus making it a usefulcombination for conducting these surgeries on a day care basis. [4][5][6] However,sufentanil's efficacyas an adjuvant to propofol in TIVAis yet to be addressed in laparoscopic cholecystectomies.
The present study seeks to assess the applicability of sufentanil, harnessingthe advantagesoutlined in earlier studies, in TIVA for laparoscopic cholecystectomy. We hypothesized that continuous infusion of sufentaniland propofolwillsuppressthe haemodynamic response to intubation and surgicalstimulation; provide perioperative haemodynamic stability with rapid recovery and excellent postoperative analgesia in patients undergoing laparoscopic cholecystectomies. This hypothesis was tested among three groups of patients undergoing laparoscopic cholecystectomy, referred henceforth as Group S1, Group S2, and Group P. We used two different concentrations of sufentanil added to propofolto determinewhich combination had maximum benefits with least side effects. Groups S1 and S2 received propofol with sufentanil added at 1µg ml -1 and 2 µg ml -1 , respectively. Group P received plain propofolwithout sufentanil. This group was intended to serve as control group.

Methods
This prospective randomized double blind study was conducted duringthe years 2006-07after approval from the institutional ethics committee and written informed consent from the patients. Sixty adult patients (18 to 65 years) of ASA physical status I or II with Mallampatiscores 1and 2;scheduled toundergo electivelaparoscopic cholecystectomywere included in the study. The study exclusion criteria were:Body weight more than 90 kg, history of hypertension on medications, history of coronary artery disease with or without percutaneous intervention on medications, history of long term analgesic use,history of psychiatric disorders, patients with severe hepatic or renal dysfunction (evident from previous medicalrecords andpresent investigations) and patients in whom NSAIDS are contraindicated.
Patients who fulfilled the inclusion criteria during the pre-anaesthetic checkup were randomly assigned into three groups of twenty each with the help of computer-generated table of random numbers. The operation theatre pharmacist assigned the concentration of sufentanil to be added to thepropofolinfusion for each group. Solutions of propofol containingdifferent concentrations ofsufentanil orno sufentanilwere prepared in 50mlsyringes by theoperation theatre pharmacist as per the randomization chart for each patient, immediately priorto induction.The interventionallocation was maskedfrom theanaesthesiologistsconductingthe study, the patients,and thenurses monitoringthe patientsin the post-anaesthesia careunit andsubsequently inthe ward.
Before start of anaesthesia, anintravenous access was secured on each patient with an 18gauge intravenous catheter for fluid and drugadministration. Pre-induction measurementof heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterialpressure (MAP) and peripheraloxygen saturation (SpO 2 ) from the anaesthesia monitor was taken as the baseline measurement. Monitoringwas continued throughout the period ofanaesthesia and included electrocardiography, pulse oximetry, non invasive arterial pressure and capnography. Patients were pre-oxygenated for 3 minutes with 100% O 2 by facemask.Anaesthesia was induced with slow i.v. injectionof sufentanil 1 µg kg -1 and continuous infusion of propofol 100 µg kg -1 min -1 . Loss of response to verbal commands was taken as the end point of induction followingwhich intermediate-acting neuromuscular blocking agent; vecuronium 0.1mg kg -1 was given. Trachea was intubated after 3minutesof maskventilation andlungs were mechanically ventilated with O 2 -Air mixture and endtidal CO 2 concentration (EtCO 2 ) was maintained between 30-40 mm Hg. HR, SBP, DBP, and SpO 2 were recorded 1, 3 and 5 minutes post-induction.
HR, SBP, DBP, SpO 2 and EtCO 2 were monitoredthroughout theintraoperative periodand recorded every 15 minutes in the observation sheet.All patients received propofolinfusion titrated to the clinical situation in a range of 75 to 125µg kg -1 min -1 . Hypotension, defined as systolicblood pressure below 80 mm Hg or mean arterial pressurebelow 60 mm Hgfor more than 5 minutes, was treated by reducingpropofolinfusion by 10µg kg -1 min -1 , but within the range of 75 to 125 µg kg -1 min -1 .Additional intravenous fluids were given as deemed appropriate. Response was reassessed at 5 minute intervalsand theabove measures continued until stabilization of blood pressure. Hypertension, defined as systolicblood pressure above 150 mm Hg or mean arterialpressure above 95 mm Hg for more than 5 minutes, was treated by giving additional sufentanil (10 µg) boluses. Sufentanil boluses (10 µg) were also given to patients in all groups when there was an increase in the heart rate by more than 20 beats per minute or mean arterial pressure by more than 15% indicating lightening of anaesthesia. Response was reassessed at 5 minute intervals and the above measures repeated untilstabilization. Neuromuscularparalysis was maintained with timelytop updoses ofvecuronium. Ten minutes before the anticipated end of surgery (at the start of skin suturing), the infusion was stopped. Total volume of propofolgiven by infusion for each patient wasrecorded. Totalamount of sufentanil andthe number of additional boluses of sufentanil given for each patient was recorded.
Residualneuromuscular blockade was reversed with neostigmine2.5mgand glycopyrrolate 0.5mgand trachea was extubated at the end of surgery following usualextubation criteria. The HR, SBP, DBPand SpO 2 were recorded 1 and 5 minutes post-extubation. All patients received slow i.v. diclofenac 75mg added to 100mlof normal saline at theend ofsurgery. Recovery timedefined astime from stoppingof propofol infusion to complete return of consciousness as assessed by the ability of the patient to open eyes and tell his/her name on questioning, and to maintain adequate spontaneous breathing (respiratory rate above 12 breaths per minute), was recorded.Duration of anaesthesia was recorded in minutes for allthe patients.
Patients were shifted to the post-anaesthesia care unit where HR, SBP, DBP, RR and SpO 2 were recorded every 15 minutes for 2hours. Allpatients were given supplemental oxygen with face mask. Postoperatively allpatients received oraldiclofenac 50mgthree times daily. Postoperative pain was assessed for 24 hours by 10-cm visual analogue scale (VAS) on which 0 cm represents no pain and 10 cm represents worst imaginable pain. 6 In post-anaesthesia care unit or in ward, patients with VAS score above 3cm received rescue analgesic, tramadol 100mg intramuscularly. Number of patients requiringrescue analgesic and the time to first rescue analgesic requirement for each patient, in first 24hours postoperatively was recorded.

Statistical analysis
Statistical analyses were conducted on measured clinicaldata usingthe Statistics Tool Box of MATLAB software. 7 Power analysis was conducted a posterior and found to be more than 90% for comparing differences between the various parameters of interest.
The statistical means of continuous variables across the three groups (age in years, weight in kilograms and durationof anaesthesiain minutes)were analyzed by one-way analysis of variance (ANOVA). Chisquare ( 2 ) test was used to test differences between the groups forcategoricalvariables(sex andASAphysical status). The generalized linear modelrepeated measures procedure was used when repeated measurements were made on the same subject, as in the case of haemodynamicmeasurements overthe perioperative period. Haemodynamic parameters (HR, SBP and DBP) were compared during the perioperative period at different time intervals -pre-induction or baseline, post-induction, intraoperative, post-extubation and postoperative, usinga Bonferroniadjusted generalized linear modelrepeated measures procedure. The model includes age, sex, weight, duration of anaesthesia, volume of propofol and sufentanil, and baseline (pre-induction) haemodynamic variables as covariates, and adjusted for potential interactions between covariates.
The total volume of propofoland totalamount of sufentanilconsumedby the three groupswas compared using one-way ANOVA and Fisher tests. The recovery time from anaesthesia was compared between the groups usinga one-wayANOVA. The time to first rescueanalgesia and the number of times rescue analgesia was given were compared usingANOVA and a  2 test. A pvalue <0.05was considered statistically significant.

Results
No patient dropped outafter enrolmentand none ofthe potentially eligible patientsmet theexclusion criteria. Patients in the three groupswere comparable as regards age,sex,ASAphysicalstatus, and duration of anaesthesia (Table 1). Weightwas significantlydifferent between the three groups (p=0.04). Themean weightwas lower in theGroup S2 compared to S1and P.

Haemodynamic parameters
The three groups were sim ilar in the baseline or pre-induction haemodynamic variables (Table 2). There was no statistically significant difference across the three groups in systolic and diastolic bloodpressures (SBP and DBP) in all the time periods studied. There was no statistically significant difference across the three groups in heart rate (HR)in allbut two time periodsstudied: postextubation and postoperative intervals ( Table 2). However this difference was notclinically significant.

Consumption of propofol and sufentanil
Patients in Group S2 (mean volume 56.80 ± 14.62 ml) required less propofol, though not statistically significant, compared with Group P (mean volume 65.50 ± 15.68 ml) and Group S1 (mean volume 58.50 ±20.42 ml) ( Table 3). The amount ofsufentanil atinduction (µg) was highest for GroupP compared to othertwo groups as the body weight was highest in this group. The total consumption ofsufentanilwassignificantly highin Group S2 (184.15±38.30 µg) compared to Group S1 (136.3±27.13 µg) and Group P (81.75±17.79 µg), as expected from the study design.

Requirement of additional boluses o f sufentanil
A total of 13 patients in Group S2 did not require anyadditionalsufentanilto maintainan adequate depth ofanaesthesia comparedto 9patients inthe other two groups ( Table 4). Thenumber of patients requiring additionalsufentanilboluses intraoperativelyin Groups P, S1 and S2, was 11, 11 and 7, respectively (Table  3). However, the total amount of sufentanil given as boluses wasnot significantlydifferent amongthose who required them (Table 3). (Table  5) was longer for Group S2 (21 ± 9 minutes) compared to S1 (14 ± 6 minutes) and P (14 ± 5 minutes). The difference in the mean recovery times across all the groups has a statistical significance ofp =0.001.

Discussion
The statisticalanalysis shows that patients in the three groups were comparable with regard to age, sex and ASAphysical status; however, they differed with  Generalized linear model repeated measures procedure, Bonferroni adjusted. The model includes age, sex, weight, duration of anesthesia, total consumption of propofol and sufentanil, and baseline (pre-induction) hemodynamic variables as covariates, and adjusted for potential interactions between covariates. * A p value <0.05 was considered as significant. on loss of consciousness during propofolinduction of anaesthesia and concluded that analgesic concentrations of sufentanil enhance the anaesthetic effect of propofoland providehaemodynamic stability.
We observed that fewer Group S2 patients required additionalboluses of sufentanil to maintain adequate depth of anaesthesia. The lesser requirement of boluses is a consequence of haemodynamic stability which in turncan be attributed to higher concentration of sufentanil (2 µg ml -1 ) used in Group S2. The bolus requirement was more frequent in the Groups P and S1, which could have contributed to the stability seen in haemodynamicparametersinthese groups.The mean decrease in the heart rate, systolic and diastolic blood pressures in perioperative period in the study groups was within a clinically acceptable range. Monk et al 1 reportedsimilarfindingsofintraoperative haemodynamic stability with sufentanil compared to other opioids. Elisabeth Hentgen et al 11 combined propofol and sufentanilin TIVAfor thyroid surgery andobserved that increasing target concentration of sufentanil provided better haemodynamic stability.
The sufentanil induction dose and propofol infusion rates used in our study were chosen based on dosage regimen suggested in earlier publications. 1,2 Previousstudies showed that increasingconcentrations of sufentanilreduce the volume of propofol consumed duringthe surgery. 3,11 Although our study did not find a statistical difference in the total consumption of  regard to body weight. The mean body weight was higher in group P compared to Groups S1and S2. This is taken into consideration in the statistical analysis of haemodynamic parameters by adjusting for potential interactions between covariates like age, sex, weight, duration of anaesthesia, volume of propofol and sufentanil, and baseline haemodynamic parameters.
No statistically significant difference was seen in thehaemodynamic parameters across thethree groups of patients in the perioperative period. Neither intubation stimulus,nor surgicalincision, norperitoneal insufflation with CO 2 hadanyinfluence onthe haemodynamic parameters in all groups. This may be attributed to the bolus of sufentanil (1µg kg -1 ) given at induction. Our study confirms that synergistic pharmacodynamic interactions between propofol and sufentanilblock responses to laparoscopic surgery. Similar observations were made in other surgical procedures 8,9 . Lysakowski et al 10 studied the effects of fentanyl and its congeners propofol, clinically, there was lesser consumption in Group S2 patients (Table 3). This marginal decrease could be due to lower body weight of the patients in this groupor dueto thehigher concentrationofsufentanil used. A larger sample size might be able to decisively answerthis question.
Recovery time was significantly prolonged (p=0.001) in Group S2 compared to the other two Groups. This delayed recovery in Group S2 patients, can be attributed to requirement of more than one sufentanil bolus in 15% of patients in addition to the higher concentration of sufentanil (2 µg ml -1 ). No significant difference was observed in Group S1 where 50% patients required one sufentanil bolus in addition to 1 µg ml -1 concentration of sufentanil, compared to Group P where about 20% patients needed multiple boluses (Table 4). Similar conclusions were drawn by Elisabeth Hentgen et al 11 in a previous study that combined increasing targetconcentrations of sufentanil with propofol in TIVA for thyroid surgery. Our findings in laparoscopic cholecystectomy confirm the conclusions reached by earlierstudies of sufentanil in other surgical procedures. It is important to note that the observed 7-minute prolongation of recovery time was clinically insignificant in our settingwhere the patients undergoing laparoscopic cholecystectomy getdischarged from the hospital on the first postoperative day.
Postoperative analgesia was better in Group S2 ( 2 p=0.01) compared with the other two groups. Patients in Group S2 had excellent 24-hour postoperative analgesia (VAS score less than 3) with least requirement of rescue analgesia. Group S1patients had good early postoperative analgesia with greater rescue analgesic requirement in the later postoperative period (more than 4 hours postoperatively). In patients who received plain propofol(Group P) there was a greater requirement of intraoperative sufentanil boluses and highest rescue analgesic requirement in the early postoperative period compared to the other two groups. Derrode et al 6 compared effects of target-controlled infusions of sufentanil and remifentanil administered along with propofol on recovery and postoperative analgesiaafter majorabdominalsurgery.They observed that quality of postoperative analgesia depends onthe opioid infusedduringsurgeryand concludedthat intraoperative use of sufentanil was very effective in providing excellent 24-hour postoperative analgesia. Our study also suggests that sufentanilat a concentration of 2µg ml -1 provides better quality of intraoperative and postoperative analgesia in laparoscopic cholecystectomy.
Sufentanil is an effective adjuvant in TIVA for laparoscopic cholecystectomy. This study concludes that bothconcentrations ofsufentanil achievethe goals ofstable haemodynamicswithout aclinically significant prolongation of recovery time. However, 2µgml -1 concentration of sufentanil added to propofol provided greater perioperativehaemodynamic stabilitywith lesser requirement for additionalboluses and excellent postoperative analgesia. The influence of sufentanilon recovery times needs further clinical trials with larger sample sizes.